Use Of 2,5-Dihydroxybenzene Compounds And Derivatives For The Treatment Of Rosacea

ABSTRACT

The present invention relates to the use of a 2,5-dihydroxybenzene derivative of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof for the treatment and/or prophylaxis of, inter alia, rosacea.

RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §119 ofES Application No. P200602218, filed Aug. 16, 2006 and of ES ApplicationNo. P200701856, filed Jul. 2, 2007. The foregoing applications, and alldocuments cited therein, are hereby incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The invention relates to the use of 2,5-dihydroxybenzene derivatives,their pharmaceutically acceptable salts and solvates, as well as isomersand prodrugs thereof for the treatment of rosacea.

BACKGROUND OF THE INVENTION

In spite of recent advances in chemotherapy and radiation, cancer is oneof the main causes of death at any age worldwide. Only, in the UnitedStates there are almost three million new cancer cases diagnosed everyyear. The overall five-year survival is close to fifty percent for allpatients, and the prognosis is still particularly bad for those patientswith advanced solid tumors.

Rosacea is a frequent ocular and facial disease usually affectingmillions of people worldwide. It is a chronic and progressive vascularskin disorder, involving mainly the malar and nasal areas of the face.Rosacea is characterized by erythema, papules, pustules, telangiectasia,facial edema, ocular lesions and in its most advanced and severe form,tissue and sebaceous gland hyperplasia leading to rhinophyma.Rhinophyma, a florid overgrowth of the tip of the nose withhypervascularity and nodularity, is an uncommon progression of rosaceawith an unknown cause. Ocular lesions, including mild conjunctivitis,burning and gritty sensation, are common. Blepharitis, the most commonocular manifestation, is a non-ulcerative condition of the eyelidmargins.

Psoriasis is a chronic disease affecting approximately 2-3% of the worldpopulation. It is characterized by epidermal cell hyperproliferation.Psoriasis symptoms include clearly defined erythematous spots covered bya characteristic crust, epidermal hyperproliferation, peeling andincomplete keratinocyte differentiation. Clinical psoriasis variantsinclude erythrodermic, seborrheic, reverse and photosensitive psoriasisand psoriasis guttata, pustular variants and Reiter's disease. There iscurrently no cure for psoriasis.

There is still a need for new effective therapies for treating cancer,treating rosacea, treating psoriasis and treating fibrosis.

SUMMARY OF THE INVENTION

The inventors have surprisingly found that 2,5-dihydroxybenzenederivatives, their pharmaceutically acceptable salts and solvates, aswell as isomers and prodrugs thereof are useful in preparing medicinalproducts for treating rosacea.

In certain embodiments, the invention provides a method for thetreatment or prophylaxis of rosacea, comprising administering to asubject in need thereof, an effective amount of a 2,5-dihydroxybenzenederivative represented by Formula (I) or a pharmaceutically acceptablesalt, solvate, isomer, or prodrug thereof, wherein the compound ofFormula (I) is:

wherein:

-   -   R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Z;    -   Y is —SO₃H, —SO₃R₃, —PO₃H, —PO₃—.X⁺, or —PO₃R₃, wherein when Y        is —SO₃H, —SO₃ ⁻.X⁺ or —SO₃R₃, then R₉ and R_(9′) are        independently selected from —OH and —OR₂, wherein at least one        of R₉ and R_(9′) is a substituted or unsubstituted        alkylsulfonyloxy group, a substituted or unsubstituted        arylsulfonyloxy group, a substituted or unsubstituted        alkylcarbonyloxy group or a substituted or unsubstituted        arylcarbonyloxy group;    -   Z is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H,        —CO₂ ⁻.X⁺ or —CO₂R₃;    -   X⁺ is an organic cation or an inorganic cation, such that the        general charge of the compound is neutral;    -   R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein when R₉ and R_(9′) are both —OR₂, then said R₉ and        R_(9′) can be the same or different;    -   R₂ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl        group, a substituted or unsubstituted alkylcarbonyl group or a        substituted or unsubstituted arylcarbonyl group;    -   R₃ is a substituted or unsubstituted alkyl group or a        substituted or unsubstituted aryl group;    -   a is a number selected from 0, 1, 2, 3, 4, 5 and 6; and    -   p is an integer selected from 0, 1, 2, 3, 4, 5 and 6.

In certain embodiments, R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y. In otherembodiments, Y is selected from —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃. In yet otherembodiments, R₃ is selected from methyl and ethyl. In some embodiments,R₉ and R_(9′) are, independently, a substituted or unsubstitutedalkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxygroup, a substituted or unsubstituted alkylcarbonyloxy group or asubstituted or unsubstituted arylcarbonyloxy group. In some embodiments,R₂ is selected from methylcarbonyl, phenylsulfonyl,4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of:5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid;2,5-bis(acetyloxy)benzenesulfonic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(acetyloxy)benzenehomosulfonic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy} benzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2-(acetyloxy)-5-hydroxybenzoic acid; 5-(acetyloxy)-2-hydroxybenzoicacid; 2,5-bis(acetyloxy)benzoic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-(acetyloxy)-5-hydroxyhomobenzoic acid;5-(acetyloxy)-2-hydroxyhomobenzoic acid; 2,5-bis(acetyloxy)homobenzoicacid; 3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamicacid); 3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceuticallyacceptable salts, solvates and prodrugs thereof.

In certain embodiments, the compound of Formula (I) is selected from:2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzene-sulfonic acid and2,5-bis(acetyloxy)benzenesulfonic acid.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of rosacea, wherein the rosacea is selectedfrom the group consisting of: erythematotelangiectatic rosacea,papulopustular rosacea, phymatous rosacea and ocular rosacea.

Advantageously, a compound of Formula (I) is administered topically. Incertain embodiments, the compound of Formula (I) is administered orally,buccally, transdermally, by inhalation, rectally, intraocularly, orotically.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of rosacea further comprisingadministration of at least one additional therapeutic agent.

Examples of suitable therapeutics agents include steroids, retinoids,antimicrobial compounds (e.g., metronidazole), antioxidants,anti-inflammatory compounds, vitamin D analogs, salicylic acid, dapsone,endothelin antagonists, immunomodulating agents, angiogenesisinhibiting/blocking agents, compounds that inhibit FGF, VEGF, EGF and/orHGF or their respective receptors, tyrosine kinase inhibitors, proteinkinase C inhibitors, vasoconstricting agents, and combinations of two ormore thereof.

In certain embodiments, the invention provides for administration of acompound of Formula (I) for the treatment and/or prophylaxis of rosacea,wherein the compound is administered at least once per week. In otherembodiments, the compound is administered at least once per day or atleast twice per day.

In certain embodiments, a compound of Formula (I) is present in apharmaceutical composition in an amount of at least about 1% w/w. Inother embodiments, the compound is present in a pharmaceuticalcomposition in an amount of at least about 2.5% w/w, at least about 5%w/w, at least about 10% w/w, or at least about 15% w/w.

In yet other embodiments, a compound of Formula (I) is administered overa period of at least about one week. In certain embodiments, thecompound is administered over a period of at least about four weeks.

These and other aspects of the present invention are explained in detailherein.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the fibrosis induced in rat adipose tissue uponsubcutaneously implanting a gelatin sponge containing only basicfibroblast growth factor (bFGF) (Figure A) or containing bFGF plus2,5-dihydroxybenzoate (Figure B) for 7 days.

FIG. 2 shows the effect of the treatment with potassium2,5-dihydroxybenzoate (gentisic acid) on the proliferation of rat gliomaC6 cells. 2,5-dihydroxybenzoate was administered or not administered(control) after seeding the C6 cells in 24-well plates (10⁴ per well)until their fixing after 48 hours. The data are expressed as mean±SEM ofthe absorbance at 595 nm, which is proportional to the number of cellsstained with crystal violet. The data were obtained from 3 cultures foreach treatment. The white bar represents the value of the control cells,whereas the black bars show the value in the presence of2,5-dihydroxybenzoate (100, 200, 500 and 1000 μM). *** indicates p<0.001with respect to the control by means of a single-factor analysis ofvariance (ANOVA) followed by a Student-Newman-Keuls post-analysis.

FIG. 3 shows the effect of the treatment with3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic acid;2,5-DHC, 10-100 μM) on the proliferation of rat glioma C6 cells. 2,5-DHCwas administered or not administered (control) after seeding the C6cells in 24-well plates (10⁴ per well) until their fixing after 48hours. The data are expressed as the mean±SEM of the absorbance at 595nm, which is proportional to the number of cells stained with crystalviolet. The data were obtained from 3 cultures for each treatment. Thewhite bar represents the value of the control cells, whereas the blackbars show the values in the presence of 2,5-DHC (10, 25, 50 and 100 μM).*** indicates p<0.001 with respect to the control by means of asingle-factor analysis of variance (ANOVA) followed by aStudent-Newman-Keuls post-analysis.

FIG. 4 shows the effect of the intraperitoneal administration ofpotassium 2,5-dihydroxybenzene sulfonate (DHBS) and potassium2,5-diacetoxybenzene sulfonate (DABS) on the progression of tumorsestablished in rats after the subcutaneous implantation of rat glioma C6cells (5×10⁵ C6 cells). The upper rows show the tumors developed in ratstreated with carrier (0.9% NaCl) (i to xi), the intermediate rows showthe tumors developed in rats treated with DHBS (i.p.; 100 mg/kg/day for10 days) (xii to xxiii), whereas the bottom rows show the tumors or theabsence thereof (indicated by N.D.) in rats treated with DABS (i.p.; 100mg/kg/day for 10 days) (xxiv to xxxvi). The tumors were removed 10 daysafter the start of the treatment, which started once the presence of atumor was verified on the fifth day after the implantation of gliomacells.

FIG. 5, Part A, shows the comparison of the volumes of the tumorsdeveloped in rats treated intraperitoneally with carrier (0.9% NaCl)(white bar), potassium 2,5-dihydroxibenzene sulfonate (DHBS; 100mg/kg/day) (black bar) or potassium 2,5-diacetoxybenzene sulfonate(DABS; 100 mg/kg/day) (striped bar) for 10 days. The data are expressedas the mean±SEM of the tumor volume of the rats of each group. Thenumber of rats of each group is indicated in brackets. * p<0.05, ***p<0.001 vs. carrier by means of a single-factor analysis of variance(ANOVA) followed by a Student-Newman-Keuls post-analysis. Part Bincludes the contingency table obtained as a result of analyzing thepossibilities of a tumor being present or absent at the end of anexperiment according to receiving treatment with DHBS (100 mg/kg/day) orwith DABS (100 mg/kg/day). The result of the analysis shows a X² valuecorresponding to p<0.05, which indicates that the probability of beingtumor-free is significantly higher in the group treated with DABS.

FIG. 6 shows the increase of apoptosis in the subcutaneous gliomas ofrats treated with potassium 2,5-diacetoxybenzene sulfonate (DABS). Theupper photograph shows a section of a tumor obtained from a rat treatedwith carrier (0.9% NaCl, i.p.) in which a low apoptosis index isobserved (A). The lower photograph shows a section of a tumor obtainedfrom a rat treated for 10 days with DABS (100 mg/kg/day, i.p.) in whicha large number of cells in an apoptosis process is observed (B). Thesections are stained with hematoxylin and eosin and observed with amagnification of 313 times. The arrows indicate the cells in anapoptosis process.

FIG. 7 shows the inhibition of human prostate cancer cell, PC-3 (A), andhuman lung cancer cell, A549 (B), proliferation by the treatment withpotassium 2,5-diacetoxybenzene sulfonate (DABS; 1-200 μM). The number ofviable cells was determined after 96 hours. The data were expressed asthe mean±SEM of the percentage of the number of cells determined in theabsence of DABS (control).

FIG. 8 shows the inhibition caused by potassium 2,5-diacetoxybenzenesulfonate (DABS; 100 mg/kg/day, i.p.) on the growth of subcutaneoushuman prostate cell tumors induced by the subcutaneous implantation ofPC-3 cells in athymic mice. The implantation of tumor cells was carriedout 10 days before starting the treatments. The carrier group receivedsaline serum injections (0.9% NaCl, i.p.). The data correspond to 10mice for each treatment. In panel A, the data are expressed as themean±SEM of the tumor volume measured every 2 days through the skin witha Vernier caliper. The volume reduction caused by DABS reachesstatistical significance. Panel B shows the effect of DABS on the weightof the tumor removed upon ending the assay. * p<0.05 by means of anunpaired Student's t test.

FIG. 9 shows the inhibition of the mitogenesis induced by fibroblastgrowth factor 1 in quiescent Balb/c 3T3 fibroblast cultures by calcium2-acetoxy-5-hydroxybenzene sulfonate (2A-5HBS) and potassium2,5-dihydroxybenzene sulfonate (DHBS).

FIG. 10 shows the inhibition of the mitogenesis induced by fibroblastgrowth factor 1 in quiescent Balb/c 3T3 fibroblast cultures by potassium5-acetoxy-2-hydroxybenzene sulfonate (5A-2HBS) and potassium2,5-dihydroxybenzene sulfonate (DHBS)

FIG. 11 shows the inhibition of the mitogenesis induced by fibroblastgrowth factor 1 in quiescent Balb/c 3T3 fibroblast cultures by potassium2,5-diacetoxybenzene sulfonate (DABS) and potassium 2,5-dihydroxybenzenesulfonate (DHBS).

FIG. 12 shows the effect of the treatment with potassium5-acetoxy-2-hydroxybenzene sulfonate (5-monoacetylated dobesilate;5A-2HBS) and potassium 2-acetoxy-5-hydroxybenzene sulfonate(2-monoacetylated dobesilate; 2A-5HBS) on the proliferation of ratglioma C6 cells. 5A-2HBS and 2A-5HBS were administered or notadministered (control) after seeding the C6 cells in 24-well plates (10⁴per well) until they were fixed after 48 hours. The data are expressedas the mean±SEM of the percentage of the absorbance at 595 nm obtainedin the control cultures, which is proportional to the number of cellsstained with crystal violet. The data were obtained from 3 cultures foreach treatment and 6 control cultures. The white bar represents thevalue of the control cells, whereas the black bar shows the value in thepresence of 5A-2HBS (500 μM) and the striped bar shows the value in thepresence of 2A-5HBS (500 μM). *** indicates p<0.001 with respect to thecontrol by means of a single-factor analysis of variance (ANOVA)followed by a Student-Newman-Keuls post-analysis.

FIG. 13 shows 2-acetoxy-5-hydroxybenzenesulfonic acid co-crystallizedwith fibroblast growth factor-1. The electronic density of the compound,contoured at 16 (panel C), allows locating and determining theorientation of the compound with respect to the protein (panels A andB), as well as asserting that the compound conserves the acetoxyl groupin position 2 when it binds to the protein. The compound occupies aplace that is very close to that described occupied by2,5-dihydroxybenzenesulfonic acid, the aromatic ring of which forms acation-π bond with the N^(ε) group of lysine 132, which is marked inpanel A as reference. Panel B shows, in the form of a mesh, the Van derWaals volume of 2-acetoxy-5-hydroxybenzenesulfonic acid, superimposedwith its representation in the form of rods. In panels A and B, theprotein surface is colored according to its electrostatic potential(light grey: negative charge; dark grey: positive charge; white: lack ofcharge).

FIG. 14 shows 5-acetoxy-2-hydroxybenzenesulfonic acid co-crystallizedwith fibroblast growth factor-1. The electronic density of the compound,contoured at 1σ (panel C), allows locating and determining theorientation of the compound with respect to the protein (panels A andB), as well as asserting that the compound conserves the acetoxyl groupin position 5 when it binds to the protein. The compound occupies aplace that is very close to that described occupied by2,5-dihydroxybenzenesulfonic acid, the aromatic ring of which forms acation-π bond with the N^(ε) group of lysine 132, which is marked inpanel A as reference. Panel B shows, in the form of a mesh, the Van derWaals volume of 2-acetoxy-5-hydroxybenzenesulfonic acid, superimposedwith its representation in the form of rods. In panels A and B, theprotein surface is colored according to its electrostatic potential(light grey: negative charge; dark grey: positive charge; white: lack ofcharge).

FIG. 15 shows 2,5-diacetoxybenzenesulfonic acid co-crystallized withfibroblast growth factor-1. The electronic density of the compound,contoured at 1σ (panel C), allows locating and determining theorientation of the compound with respect to the protein (panels A andB), as well as asserting that the compound conserves the acetoxyl groupsin positions 2 and 5 when it binds to the protein. The compound occupiesa place that is very close to that described occupied by2,5-dihydroxybenzenesulfonic acid, the aromatic ring of which forms acation-π bond with the N^(ε) group of lysine 132, which is marked inpanel A as reference. Panel B shows, in the form of a mesh, the Van derWaals volume of 2,5-diacetoxybenzenesulfonic acid, superimposed with itsrepresentation in the form of rods. In panels A and B, the proteinsurface is colored according to its electrostatic potential (light grey:negative charge; dark grey: positive charge; white: lack of charge).

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this description, it must be understood that thefollowing terms have the following meanings unless otherwise indicated.

The term “patient” relates to animals, preferably mammals, morepreferably human beings, and includes men and women, and children andadults.

The expression “effective amount” relates to the amount of the compoundand/or composition which is effective for achieving its desired purpose.

The terms “treat” or “treatment” relate to the use of the compounds orcompositions of the present invention in a prophylactic manner toprevent the symptoms of the disease or disorder, or in a therapeuticmanner to improve an existing condition.

The term “rosacea” relates to a chronic skin disease that causes rednessand swelling, primarily on the face. Other areas that can be affectedare the scalp, neck, ears, chest and back. Sometimes, rosacea affectsthe eyes. Rosacea affects 10-20% of the 30-60 year-old population,specially among fair-skinned persons and people of northern European andCeltic ancestry. Rosacea and acne are two independent skin diseases.Rosacea is associated to redness and erythema while acne is associatedto hyperseborrhea. Papules, pustules, cysts and scars can be found inacne while only papules and pustules may be present in rosacea (duVivier A and McKee PH. In: Atlas of Clinical Dermatology, 2^(nd)edition. New York, Gower Medical Publishing, 1995). According to theNational Rosacea Society (Wilkin J et al. J Am Acad Dermatol, 2002),rosacea can be classified into: erythematotelangiectatic rosacea, whenerythema and telangiectasia are the main features; papulopustularrosacea, when papules and pustules are present; phymatous rosacea whenthere is a hypertrophy of sebaceous glands that can alter the shape ofthe nose (rhinophyma) and ocular rosacea when the eyes are affected.

The term “chemotherapy” relates to the use of a chemotherapeutic agentfor treating a cancer.

The term “radiation therapy” or “radiotherapy” relates to the medicaluse of ionization radiation as part of the cancer treatment to controlcancer cells.

The expression “cancer immunotherapy” relates to the stimulation of theimmune system to reject or destroy tumors, and includes but is notlimited to immunotherapy with bacillus Calmette-Guerin (BCG), topicalimmunotherapy, immunotherapy by injection and the like.

The term “therapeutic agent” includes any therapeutic agent that can beused to treat or prevent the diseases described herein. “Therapeuticagents” include but are not limited to chemotherapeutic agents,steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, NMDA receptor antagonists, endothelinantagonists, immunomodulating agents, vitamin D analogs, salicylic acid,and the like. A therapeutic agent includes pharmaceutically acceptablesalts thereof, prodrugs and pharmaceutical derivatives thereof.

The term “antimicrobial compound” relates to any compound altering thegrowth of bacteria, fungi or viruses whereby the growth is prevented,modified, reduced, stabilized, inhibited or stopped. Antimicrobialcompounds can be microbicides or microbiostatic agents and include butare not limited to antibiotics, semi-synthetic antibiotics, syntheticantibiotics, antifungal compounds, antiviral compounds and the like.

The term “antifungal compound” relates to any compound altering thegrowth of fungi whereby the growth is prevented, modified, reduced,stabilized, inhibited or stopped.

The term “antiviral compound” relates to any compound altering thegrowth of viruses whereby the growth is prevented, modified, altered,stabilized, inhibited or stopped.

The term “antioxidant” relates to and includes any compound that canreact and inactivate a free radical, including but not limited to freeradical eliminators, iron chelating agents, small molecule antioxidantsand antioxidant enzymes and the like.

The term “taxane” relates to any compound containing the central carbonframe represented by Formula A:

The term “NSAIDs” relates to a non-steroidal anti-inflammatory compoundor to a non-steroidal anti-inflammatory drug. NSAIDs inhibitcyclooxygenase, the enzyme responsible for the biosynthesis ofprostaglandins and certain autacoid inhibitors, including inhibitors ofseveral cyclooxygenase isozymes (including but not limited tocyclooxygenase 1 and 2), and inhibitors of both cyclooxygenase andlipoxygenase.

The term “organic cation” relates to a positively charged organic ion.Examples of organic cations include ammonium cations substituted withalkyl or unsubstituted ammonium cations, primary, secondary and tertiaryamines, alkylamines, arylamines, cyclic amines,N,N′-dibenzylethylenediamine and the like.

The term “inorganic cation” relates to a positively charged metal ion.Examples of inorganic cations include Group I metal cations such as, forexample, sodium, potassium, magnesium, calcium and the like.

The expression “general charge” means the general or total charge of thecompound.

The term “topical” relates to the administration of a compound by meansof the application on the body surface and includes but is not limitedto transdermal administration and administration through the mucousmembrane.

The term “transdermal” relates to the administration of a compoundpassing through the skin into the blood stream.

The expression “through the mucous membrane” relates to theadministration of a compound passing through the mucous tissue into theblood stream.

The term “parenteral” relates to the administration of a compound bysubcutaneous, intravenous, intramuscular, intracardiac, intradermal,intraperitoneal, intrathecal or intracisternal injection, and alsoincludes local and systemic infusion techniques.

The expression “penetration enhancement” or “permeation enhancement”relates to an increase in the permeability of the skin or mucous tissuefor a pharmacologically active compound selected such that it increasesthe amount and/or the rate at which the compound penetrates the skin ormucous membranes or traverses the skin and mucous membranes.

“Excipients” or “carriers” relate to suitable carrier materials for theadministration of a compound and include any of said materials known inthe art such as for example, any liquid, gel, solvent, liquid diluent,solubilizer or the like, which is not toxic and does not interact withany component of the composition in a harmful manner.

The expression “sustained release” relates to the release of an activecompound and/or composition such that the blood levels of the activecompound are maintained in a desirable therapeutic interval for a timeperiod. The sustained release formulation can be prepared using anyconventional method known by persons skilled in the art to obtain thedesired release characteristics.

The term “ester derivative of a compound of formula (I)” refers to thecompound of formula (I) wherein at least one of R₉ and R_(9′) is anester group. For example, the ester derivative of 2,5-dihydroxybenzenesulfonic acid or dobesilate ester derivative refers to the compound2,5-dihydroxybenzene sulfonic acid (dobesilate) wherein at least one ofthe hydroxyl groups has been esterified.

The term “ester of a compound of formula (I)” refers to an ester of thesulfonic or carboxylic acid group at position 1. For example, the esterof 2,5-dihydroxybenzensulfonic acid or ester of dobesilate refers to anester of the sulfonic acid group at position 1.

The following terms have the indicated meaning in the definitions of thecompounds described herein:

“Alkyl” relates to a linear or branched chain hydrocarbon radical formedby hydrogen and carbon atoms, which does not contain unsaturations, withone to twelve, preferably one to eight, more preferably one to sixcarbon atoms and which is joined to the rest of the molecule by a singlebond, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl,n-pentyl, etc.

“Alkenyl” relates to a linear or branched chain hydrocarbon radicalformed by hydrogen and carbon atoms, containing at least oneunsaturation, with two to twelve, preferably two to eight, morepreferably two to six carbon atoms and which is joined to the rest ofthe molecule by a single bond.

“Cycloalkyl” relates to a saturated carbocyclic ring having betweenthree and eight, preferably three and six carbon atoms. It can have abridged structure. Suitable cycloalkyl groups include but are notlimited to cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

“Aryl” relates to an aromatic hydrocarbon radical having from six to tencarbon atoms such as phenyl or naphthyl.

“Aralkyl” relates to an aryl group joined to the rest of the molecule byan alkyl group such as benzyl and phenethyl.

“Heterocycle” relates to a stable ring having 3 to 15 members consistingof carbon atoms and between one and five heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur, preferably a ringhaving 4 to 8 members with one, two, three or four heteroatoms, morepreferably a ring having 5 or 6 members with one, two or threeheteroatoms. For the purposes of this invention, the heterocycle can bea monocyclic, bicyclic or tricyclic ring system, which can include fusedring systems; bridged structures; and the nitrogen, carbon or sulfuratoms in the heterocyclyl radical can optionally be oxidized; thenitrogen atom can optionally be quaternized; and the heterocyclylradical can be partially or completely saturated or be aromatic.Examples of such heterocycles include but are not limited to azepines,benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole,piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.

Unless otherwise indicated, the alkyl, cycloalkyl, alkenyl, alkynyl,aryl, aralkyl and heterocycle radicals can optionally be substitutedwith one, two or three substituents such as halo, alkyl, alkenyl,alkynyl, cycloalkyl, hydroxy, alkoxy, sulfoxy, O-benzyl, O-benzoyl,carboxy, alkylcarboxy, arylcarboxy, alkylcarbonyl, arylcarbonyl, cyano,carbonyl, acyl, alkoxycarbonyl, amino, alkylamino, dialkylamino,arylamino, diarylamino, alkylarylamino, imino, alkylsulfinyl, amidyl,carbamoyl, sulfonamido, nitro, nitrite, nitrate, thionitrate andcarboxamido.

The term “alkoxycarbonyl” relates to compounds with the Formula—C(═O)O—, in which the C-end is joined to the molecule and the O-end isjoined to a carbon atom to form an ester function. Said carbon atom canbe part of an alkyl, alkenyl, cycloalkyl, alkynyl, aryl, aralkyl orheterocyclyl group.

The term “alkoxycarbonylalkyl” relates to compounds of Formula —C(═O)O—defined previously, in which the C-end is joined to the molecule throughan alkyl group. The terms “aryloxy- arylalkoxy- oralkylarylalkoxy-carbonylalkyl” will be interpreted in a manner similarto the definition of “alkoxycarbonylalkyl”.

The term “arylalkyl” relates to an aryl radical, as defined herein,joined to an alkyl radical, as defined herein. Examples of arylalkylgroups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl and the like.

The term “alkylaryl” relates to an alkyl group, as defined herein, towhich an aryl group as defined herein is joined. Examples of alkylarylgroups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl and the like.

The term “alkylsulfonyl” relates to R₅₀—S(O)₂—, where R₅₀ is a loweralkyl group as defined herein.

The term “arylsulfonyl” relates to R₅₅—S(O)₂—, where R₅₅ is an arylgroup as defined herein.

The term “alkylsulfinyl” relates to R₅₅—S(O)—, where R₅₅ is an arylgroup as defined herein.

The term “arylsulfinyl” relates to R₅₅—S(O)—, where R₅₅ is an aryl groupas defined herein.

The term “sulfonamide” relates to —S(O)₂—N(R₅₁)(R₅₇), where R₅₁ and R₅₇are each independently a hydrogen atom, an alkyl group, an aryl group,heterocyclic group, as defined herein, or R₅₁ and R₅₇ together form aheterocyclic ring, a cycloalkyl group, or a bridged cycloalkyl group, asdefined herein.

The term “alkylsulfonamide” relates to a sulfonamido group as definedherein, bonded to an alkyl group as defined herein.

The term “arylsulfonamide” relates to a sulfonamido group as definedherein, bonded to an aryl group as defined herein.

The term “alkylcarbonyl” relates to R₅₂—C(O)₂—, where R₅₂ is an alkylgroup as defined herein.

The term “arylcarbonyl” relates to the R₅₅—C(O)— radical, where R₅₅ isan aryl group as defined herein.

The term “carboxamide” relates to the —C(O)N(R₅₂)(R₅₈) radical, whereR₅₂ and R₅₈ are each independently a hydrogen atom, an alkyl group, anaryl group, or a heterocyclic group, as defined herein, or R₅₁ and R₅₇together from a heterocyclic ring, a cycloalkyl group, or a bridgedcycloalkyl group, as defined herein.

The term “carboxylic ester” relates to —C(O)OR₅₉, where R₅₉ is an alkylgroup, an aryl group or a heterocyclic group, as defined herein.

The term “alkoxyalkyl” relates to an alkoxy group as defined herein,bonded to an alkyl group as defined herein. Examples of alkoxyalkylgroups are methoxymethyl, methoxyethyl, isopropoxymethyl and the like.

The term “amine” relates to any organic compound containing at least onebasic nitrogen atom.

The term “prodrug” relates to compounds which are quickly transformed invivo into pharmacologically active compounds. The design of prodrugs isgenerally studied in Hardma et al. (Eds.), Goodman and Gilman's ThePharmacological Basis of Therapeutics, 9th ed., pages 11-16 (1996). Anin-depth study is carried out in Higuchi et al., Prodrugs as NovelDelivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.),Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press (1987).

The compounds of the invention having one or more asymmetric carbonatoms can exist as optically pure enantiomers, pure diastereoisomers,mixtures of enantiomers, mixtures of diastereoisomers, racemic mixturesof enantiomers, diastereoisomeric racemates or mixtures ofdiastereoisomeric racemates. It must be understood that the inventionforesees and includes all these isomers and mixtures thereof.

In a first aspect, the present invention relates to the use of acompound of Formula (I) or pharmaceutically acceptable salt or solvate,isomer or prodrug thereof in preparing a medicament for the treatmentand/or prophylaxis of rosacea, wherein the compound of Formula (I) is:

wherein:

-   -   R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Z;    -   Y is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃;    -   Z is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H,        —CO₂ ⁻.X⁺ or —CO₂R₃;    -   X⁺ is an organic cation or an inorganic cation, such that the        general charge of the compound is neutral;    -   R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein when R₉ and R_(9′) are both —OR₂, then said R₉ and        R_(9′) can be the same or different;    -   R₂ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl        group, a substituted or unsubstituted alkylcarbonyl group or a        substituted or unsubstituted arylcarbonyl group, a substituted        or unsubstituted arylalkyl group, a substituted or unsubstituted        alkylarylsulfonyl group, a substituted or unsubstituted        arylalkylsulfonyl group, a substituted or unsubstituted        aryloxyalkyl group, a carboxy group, a substituted or        unsubstituted alkoxycarbonyl group, a substituted or        unsubstituted carboxyalkyl group, particularly —CH₂—COOH, or a        substituted or unsubstituted alkoxy- aryloxy- arylalkoxy- or        alkylaryloxy-carbonylalkyl group, particularly —CH₂—COOR_(S),    -   R₃ is a substituted or unsubstituted alkyl group or a        substituted or unsubstituted aryl group;    -   a is number selected from 0, 1, 2, 3, 4, 5 and 6;    -   p is an integer selected from 0, 1, 2, 3, 4, 5 and 6,        with the proviso that when Y is —SO₃H, —SO₃ ⁻.X⁺ or —SO₃R₃, then        R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein at least one of R₉ and R_(9′) is a substituted or        unsubstituted alkylsulfonyloxy group, a substituted or        unsubstituted arylsulfonyloxy group, a substituted or        unsubstituted alkylcarbonyloxy group or a substituted or        unsubstituted arylcarbonyloxy group.

In a particular embodiment, 2,5-dihydroxybenzene derivatives of theinvention or any of the pharmaceutically acceptable salts thereof arethose that are represented by Formula (I) comprising dobesilate estersderivatives or pharmaceutically acceptable salts or esters thereof forthe treatment of rosacea.

The cation X⁺ in the compounds of Formula (I) can be any physiologicallyacceptable cation known by a person skilled in the art, and includes butis not limited to those described in Heinrich Stahl, Camille G. Wermuth(eds.), “Handbook of Pharmaceutical Salts Properties, Selections andUse”, Verlag Helvetica Chimica Acta, Zurich, Switzerland, Wiley-VCH,Weinheim, Germany, 2002; the entire descriptions of which areincorporated as a reference herein. Cation X is selected such that thetotal charge of the compounds of Formula (I) is neutral.

In a particular embodiment of the invention R₁ is —(CH₂)_(a)Y or—CH═CH—(CH₂)_(p)Y. More particularly, Y is selected from —SO₃H, —SO₃R₃.

In another particular embodiment, R₃ is selected from methyl and ethyl,isopropyl and C₆H₅—, more particularly methyl and ethyl.

In another particular embodiment, at least one of R₉ and R_(9′) are,independently, a substituted or unsubstituted alkylsulfonyloxy group, asubstituted or unsubstituted arylsulfonyloxy group, a substituted orunsubstituted alkylcarbonyloxy group or a substituted or unsubstitutedarylcarbonyloxy group.

Even, in another particular embodiment, R₂ is selected frommethylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl,benzyl and phenyl.

In another particular embodiment of the invention, R₂ is selected fromacetyl (—C(O)CH₃), tosyl (—SO₂—C₆H₄—CH₃) and p-chlorophenoxyisobutyryl(—C(O)—C(CH₃)₂—O—C₆H₄C1).

In an embodiment of the invention, the inorganic cation is sodium,potassium, lithium, calcium or magnesium.

In another embodiment of the invention, the organic cation is[NH_(4-p)Rp]⁺, where p in each case is independently selected from aninteger from 0 to 4; and R is an alkyl group of one to six carbon atomssuch as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl or n-pentyl.

In another embodiment of the invention, the organic cations are adiethylamino group [H₂N⁺ (C₂H₅)₂], piperazine or pyridine.

In other embodiments of the invention, the compounds of Formula (I) andpharmaceutically acceptable salts thereof are:

where:

-   -   n is an integer from 1 to 2;    -   m is an integer from 1 to 2; and    -   X, R₂ and R₃ are as defined herein.

In a preferred embodiment, the compound of Formula (I) is selected fromthe group consisting of:

-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2-(acetyloxy)-5-hydroxybenzenesulfonic acid;-   5-(acetyloxy)-2-hydroxybenzenesulfonic acid;-   2,5-bis(acetyloxy)benzenesulfonic acid;-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy} benzenehomosulfonic    acid;-   2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;-   5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;-   2,5-bis(acetyloxy)benzenehomosulfonic acid;-   3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic    acid);-   3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic    acid;-   3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic    acid;-   3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;-   3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid;-   3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;-   3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;-   3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;-   3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;-   3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid;

and pharmaceutically acceptable salts, solvates and prodrugs thereof.

Particularly preferred are the compounds2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid and2,5-bis(acetyloxy)benzene sulfonic acid.

In a particular embodiment, the rosacea is selected fromerythematotelangiectatic rosacea, papulopustular rosacea, phymatousrosacea and ocular rosacea.

The compounds of Formula (I) can be synthesized by a person skilled inthe art using conventional methods available on the market. Thesynthesis of the compounds of Formula (I) is described, for example, inU.S. Pat. No. 5,082,941; and “The Merck Index” 13th edition, Merck &Co., R. Railway, N.J., USA, 2001; U.S. Pat. Nos. 5,082,841, 4,814,110,4,613,332 and 4,115,648; the entire descriptions of which areincorporated as a reference herein.

The compounds of Formula (I) can also be in the form of solvates,particularly in the form of hydrates. The compounds of Formula (I) aswell as their solvates can be prepared by a person skilled in the artusing conventional methods and reagents available on the market.

Although it was previously indicated in one of the preferred embodimentswith respect to the definition of cation X, the scope of this inventionincludes any salt thereof, particularly any pharmaceutically acceptablesalt of the compound. The term “pharmaceutically acceptable salts”includes the metal salts or the addition salts which can be used indosage forms. For example, the pharmaceutically acceptable salts of thecompounds provided herein can be acid addition salts, base additionsalts or metal salts, and can be synthesized from parent compoundscontaining a basic or acid residue by means of conventional chemicalprocesses. Such salts are generally prepared, for example, by reactingthe free acid or base forms of these compounds with a stoichiometricamount of the suitable base or acid in water or in an organic solvent orin a mixture of both. Non-aqueous media are generally preferred, such asether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Examples ofacid addition salts include mineral acid additions salts such as, forexample, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,phosphate, organic acid addition salts such as, for example, acetate,maleate, fumarate, citrate, oxalate, succinate, tartrate, malate,mandelate, methanesulfonate and p-toluenesulfonate. Examples of alkaliaddition salts include inorganic salts such as, for example, ammoniumsalts and organic alkaline salts such as, for example, diethylamine,ethylenediamine, ethanolamine, N,N-dialkylenethanolamine,triethanolamine, glutamine and basic amino acid salts. Examples of metalsalts include, for example, sodium, potassium, calcium, magnesium,aluminium and lithium salts.

The term “pharmaceutically acceptable” relates to molecular entities andcompositions that are physiologically tolerable and do not normallycause an allergic reaction or a similar adverse reaction, such asgastric discomfort, dizziness and the like, when administered to humans.As used herein, the term “pharmaceutically acceptable” preferably meansthat it is approved by a regulatory agency of the federal or stategovernment or listed in the US pharmacopoeia or another pharmacopoeia,generally recognized for its use in animals and more particularly inhuman beings.

It will be evident for persons skilled in the art that the scope of thepresent invention also comprises salts that are not pharmaceuticallyacceptable as possible means for obtaining pharmaceutically acceptablesalts.

According to this invention, the term “solvate” must be understood tomean any form of the active compound according to the invention havinganother molecule (most likely a polar solvent) joined thereto by meansof a non-covalent bond. Examples of solvates include hydrates andalcoholates, preferably C₁-C₆ alcoholates, methanolate for example.

The pharmaceutically acceptable salts of the compounds of Formula (I)can be obtained from organic or inorganic acids or bases by conventionalmethods by reacting the suitable acid or base with the compound.

In a particular embodiment of the invention, the 2,5-dihydroxybenzenederivatives of the invention can optionally be used combining them withone another. Said combinations can be in the same formulation or informulations which would be sequentially used.

In certain embodiments, the invention provides a composition comprisingan ester derivative of those comprised in Formula (I), particularly adobesilate ester derivative, such as2-acetyloxy-5-hydroxybenzenesulfonic acid, 5-acetyloxy-2-hydroxybenzenesulfonic acid, or 2,5-bis-acetyloxybenzene sulfonic acid. In someembodiments, it will be desirable to formulate a composition of theinvention with an active ingredient which is a dobesilate esterderivative, for example, where the ester derivative shows greatertherapeutic efficacy than the original compound in the treatment orprevention of a condition described herein. In other embodiments, theinvention includes the use of a dobesilate ester derivative as aprodrug, for example, to treat a condition described herein, in whichthe ester is metabolized to the original compound in a patient for thepurpose of reaching therapeutic efficacy in the patient.

The invention provides compositions comprising at least one compound ofFormula (I) and at least one additional therapeutic agent, including butnot limited to a steroid, a retinoid, an antimicrobial compound, anantioxidant, an anti-inflammatory compound, a vitamin D analog,salicylic acid, an endothelin antagonist, an immunomodulating agent, anangiogenesis inhibiting/blocking agent, a compound inhibiting FGF, VEGF,EGF and HGF or their respective receptors, a tyrosine kinase inhibitor,a protein kinase C inhibitor, metronidazole, dapsone, vasoconstrictingagents and a combination of two or more of them.

In an embodiment of the invention, the therapeutic agent includesanti-inflammatory compounds. The invention also provides saidcompositions in a pharmaceutically acceptable carrier.

The compounds of Formula (I) can optionally be used together with one ormore additional therapeutic agents; such as a steroid, a retinoid, anantimicrobial compound, an antioxidant, an anti-inflammatory compound, avitamin D analog, salicylic acid, an endothelin antagonist, animmunomodulating agent, an angiogenesis inhibiting/blocking agent, acompound inhibiting FGF, VEGF, EGF and HGF or their respectivereceptors, a tyrosine kinase inhibitor, a protein kinase C inhibitor,metronidazole, dapsone, vasoconstricting agents and a combination of twoor more of them to treat rosacea.

Suitable steroids include but are not limited to budesonide,dexamethasone, corticosterone, prednisolone and the like. Suitablesteroids are described in more detail in the literature, such as in TheMerck Index on CD-ROM, 13th Edition. In a preferred embodiment of theinvention, the steroids are dexamethasone, prednisolone andcorticosteroids.

Suitable retinoids include but are not limited to natural and syntheticanalogs of vitamin A (retinol), vitamin A aldehyde (retinal), vitamin Aacid (retinoic acid (RA)), including all the trans-, 9-cis- and13-cis-retinoic acids), tretinoin, isotretinoin, alitretinoin,etretinate, acitretin, tazarotene, bexarotene and the like. Suitableretinoids are also described in document EP 0379367 A2, U.S. Pat. Nos.4,887,805; 4,888,342; 5,514,825; 5,698,700; 5,696,162; 5,688,957;5,677,451; 5,677,323; 5,677,320; 5,675,033; 5,675,024; 5,672,710;5,688,175; 5,663,367; 5,663,357; 5,663,347; 5,648,514; 5,648,503;5,618,943; 5,618,931; 5,618,836; 5,605,915; 5,602,130; 5,648,563;5,648,385; 5,618,839; 5,559,248; 5,616,712; 5,616,597; 5,602,135;5,599,819; 5,556,996; 5,534,516; 5,516,904; 5,498,755; 5,470,999;5,468,879; 5,455,265; 5,451,605; 5,343,173; 5,426,118; 5,414,007;5,407,937; 5,399,586; 5,399,561; 5,391,753 and the like; the entiredescriptions of which are incorporated herein as a reference. In somepreferred embodiments of the invention, the retinoids are retinol,retinal, retinoic acid, tretinoin, isotretinoin or alitretinoin.

Suitable antimicrobial compounds include but are not limited tomacrolides such as, for example, azithromycin, clarithromycin,dirithromycin, erythromycin, milbemycin, troleandomycin and the like;monobactams such as, for example, aztreonam and the like; tetracyclinessuch as, for example, demeclocycline, doxycycline, minocycline,oxytetracycline, tetracycline and the like; aminoglycosides such as, forexample, amikacin, gentamicin, kanamycin, neomycin, netilmicin,paromomycin, streptomycin, tobramycin and the like; carbacephems suchas, for example, loracarbef and the like; carbapenems such as, forexample, ertapenem, imipenem, meropenem and the like; penicillins suchas, for example, amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin,penicillin, piperacillin, ticarcillin and the like; polypeptides suchas, for example, bacitracin, colistin, polymyxin B and the like;beta-lactamase inhibitors; cephalosporins such as, for example,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, cefadroxil,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefazolin,cephalaxin, cefepime and the like; quinolones such as, for example,ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin,moxifloxacin, norfloxacin, ofloxacin, trovafloxacin and the like;streptogramins; sulfonamides such as, for example, mafenide, prontosil,sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazine,sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole and the like;and the combination drugs such as, for example, sulfamethoxazole andtrimethoprim and the like. Suitable antimicrobial compounds of theinvention are more fully described in the literature, such as in Goodmanand Gilman, The Pharmacological Basis of Therapeutics (9th Edition),McGraw-Hill, (1996); Merck Index on CD-ROM, 13th Edition; STN Express,file phar and file registry, the entire descriptions of which areincorporated herein as a reference. In some preferred embodiments of theinvention, the antimicrobial compounds are tetracycline, erythromycin orclindamycin.

Suitable antioxidants include but are not limited to free radicaleliminators, iron chelating agents, small molecule antioxidants andantioxidant enzymes and the like. Suitable iron chelating agents includebut are not limited to deferoxamine, deferiprone, dithiocarbamate,ethylenediaminetetraacetic acid and the like. Suitable small moleculeantioxidants include but are not limited to compounds of hydralazine,glutathione, ascorbic acid (vitamin C), vitamin E, cysteine,N-acetyl-cysteine, β-carotene, ubiquinone, ubiquinol-10, tocopherols,coenzyme Q, superoxide dismutase mimetics such as, for example,2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxidecompounds; 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPOL),M-40401, M-40403, M-40407, M-40419, M-40484, M-40587, M-40588 and thelike. Suitable antioxidant enzymes include but are not limited tosuperoxide dismutase, catalase, glutathione peroxidase, NADPH oxidaseinhibitors such as, for example, apocynin, aminoguanidine, ONO 1714,SI7834 (a benzo(b)pyran-4-one derivative) and the like; xanthine oxidaseinhibitors such as, for example, allopurinol, oxypurinol, amflutizole,diethyldithiocarbamate, 2-styrylchromones, crisine, luteolin,kaempferol, quercetin, myricetin, isorhamnetin, benzophenones such as2,2′,4,4′-tetrahydroxybenzophenone,3,4,5,2′,3′,4′-hexahydroxybenzophenone and 4,4′-dihydroxybenzophenone;benzothiazinone analogs such as 2-amino-4H-1,3-benzothiazin-4-one,2-guanidine-4H-1,3-benzothiazin-4-one and rhodanine; N-hydroxyguanidinederivative such as PR5(1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine);6-formylpterin and the like. The antioxidant enzymes can be released bygene therapy in the form of a viral vector and/or a non-viral vector.Suitable antioxidants are described in more detail in the literature,such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics(9th Edition), McGraw-Hill, 1995; and The Merck Index on CD-ROM,Thirteenth Edition; and in STN Express, file phar and file registry. Insome preferred embodiments, the antioxidants are ascorbic acid, vitaminE, apocynin, hydralazine compounds or superoxide dismutase mimetics.

Suitable NSAIDs include but are not limited to acetaminophen,acemetacin, aceclofenac, alminoprofen, amfenac, bendazac, benoxaprofen,bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac,diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen,fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen,indometacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac,loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin,pirazolac, pirprofen, pranoprofen, protizinic acid, salicylamide,sulindac, suprofen, suxibuzone, tiaprofenic acid, tolmetin, xenbucin,ximoprofen, zaltoprofen, zomepirac, aspirin, acemetacin, bumadizone,carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamicacid, flunixin, gentisic acid, ketorolac, meclofenamic acid, mefenamicacid, mesalamine, prodrugs thereof, and the like. Suitable NSAIDs aremore fully described in the literature, such as in Goodman and Gilman,The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill,1995, pages 617-657; the Merck Index on CD-ROM, 13th Edition; and inU.S. Pat. Nos. 6,057,347 and 6,297,260 issued to NitroMed. Inc., theentire descriptions of which are incorporated herein as a reference. Insome preferred embodiments, the NSAIDs are acetaminophen, diclofenac,flurbiprofen, ibuprofen, indometacin, ketoprofen, naproxen or aspirin.

Suitable N-methyl-D-aspartate (NMDA) receptor antagonists include butare not limited to ketamine, dextromethorphan, memantine, amantadine,nitrous oxide, gacyclidine and the like. In some preferred embodiments,the NMDA receptor antagonist is dextromethorphan.

Suitable endothelin antagonists include but are not limited toatrasentan, bosentan, darusentan, enrasentan, sitaxsentan, sulfonamide,tezosentan, BMS 193884, BQ-123, SQ 28608 and the like. Suitableendothelin antagonists are described in more detail in the literature,such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics(9th Edition), McGraw-Hill, 1995; and The Merck Index on CD-ROM,Thirteenth Edition; and in STN Express, file phar and file registry.

Suitable immunomodulating agents include but are not limited tointerferon a Jib, autologous granulocyte-macrophage colony stimulatingfactor, APC 8015 (Provenge), anti-cancer vaccines, anti-senseoligonucleotides, bacillus Calmette-Guerin (BCG) and the like.

Suitable vitamin D analogs include but are not limited to vitamin D3analogs such as colecalciferol, calcidiol, calcitriol and the like.

In an additional aspect, the invention relates to a method for thetreatment and/or prophylaxis of rosacea which comprises administering,to a patient who needs it, an effective amount of a compound of Formula(I), a pharmaceutically acceptable salt and solvate, isomer or prodrugthereof described herein. An effective amount of at least one2,5-dihydroxybenzene compound of Formula (I) can be administered to thepatient for example. In another embodiment, an effective amount of atleast one 2,5-dihydroxybenzene compound of Formula (I), and at least oneadditional therapeutic agent including but not limited to those such as,for example, a steroid, a retinoid, an antimicrobial compound, anantioxidant, an anti-inflammatory compound, a vitamin D analog,salicylic acid, an endothelin antagonist, an immunomodulating agent, anangiogenesis inhibiting/blocking agent, a compound inhibiting FGF, VEGF,EGF and HGF or their respective receptors, a tyrosine kinase inhibitor,a protein kinase C inhibitor, metronidazole, dapsone, vasoconstrictingagents, and a combination of two or more of them.

The 2,5-dihydroxybenzene compounds and/or additional therapeutic agentscan be administered separately or as components of the same compositionin one or more pharmaceutically acceptable carriers.

Another aspect of the invention is that the 2,5-dihydroxybenzenederivatives of Formula (I) can optionally be used by combining them withone another. Said combinations can be in the same formulation or informulations which will be sequentially used.

When administered separately, the 2,5-dihydroxybenzene compound ofFormula (I) can be administered approximately at the same time as partof the overall treatment regimen, i.e. as a combination therapy. Theexpression “approximately at the same time” includes administering the2,5-dihydroxybenzene compound simultaneously, sequentially, at the sametime, at different times in the same day, on different days, as long asit is administered as part of an overall treatment regimen, i.e. acombination therapy or a therapeutic cocktail.

When administered, the compounds and compositions of the invention canbe administered in combination with pharmaceutically acceptable carriersand in the dosages described herein. When the compounds and compositionsof the invention are administered as a combination of at least one2,5-dihydroxybenzene compound of formula (I) and/or at least oneadditional therapeutic agent, they can also be used in combination withone or more additional compounds which are known to be effective againstthe specific pathology set as a treatment target. The therapeutic agentsand/or the different additional compounds can be administeredsimultaneously with, after or before the administration of the2,5-dihydroxybenzene compound.

In an embodiment of the invention, the 2,5-dihydroxybenzene compounds offormula (I) are administered topically, transdermally, orally, buccally,parenterally, by inhalation, rectally (for example, with the use ofsuppositories), intraocularly or otically, in unit dosage formulationscontaining excipients, adjuvants, and conventional, non-toxicpharmaceutically acceptable carriers, as desired. In a particularembodiment, 2,5-dihydroxybenzene compounds of formula (I) areadministered by topical application.

The solid dosage forms for oral administration can include capsules,sustained release capsules, tablets, sustained release tablets, chewabletablets, sublingual tablets, effervescent tablets, pills, suspensions,powders, granules and gels. The active compounds in said solid dosageforms can be mixed with at least one inert diluent such as sucrose,lactose or starch. Said dosage forms can also comprise, as in normalpractice, additional substances different from the inert substances, forexample, lubricants such as magnesium stearate. In the case of capsules,tablets, effervescent tablets and pills, the dosage forms can alsocomprise buffering agents. The soft gelatin capsules can be preparedsuch that they contain a mixture of the active compositions or compoundsof the invention and vegetable oil. Hard gelatin capsules can containgranules of the active compound combined with a solid, powdery carrier,such as lactose, sucrose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives and gelatin. The tablets andpills can be prepared with enteric coatings.

The liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, syrups and elixirscontaining inert diluents commonly used in the art, such as water. Saidcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspension agents, and sweeteners, flavoring agents andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention stand out among rectal and vaginaladministration forms; such suppositories can be prepared by mixing thecompounds or compositions with a suitable non-irritating excipient suchas cocoa butter and polyethyleneglycols which are solid at roomtemperature but liquid at rectal temperature, such that they will meltin the rectum and vagina and release the compounds and compositions.

The injectable preparations, for example, injectable and sterile aqueousor oily suspensions can be formulated according to the known art usingsuitable dispersing agents, wetting agents and/or suspension agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a non-toxic, parenterally acceptable diluent orsolvent, for example, a solution in 1,3-butanediol. Included among theacceptable carriers and solvents which can be used are water, Ringersolution, and isotonic sodium chloride solution. The sterile fixed oilsare also conventionally used as solvents or suspension mediums.

The topical administration of the compounds and compositions of theinvention can be in the form of creams, gels, lotions, liquids,ointments, spray solutions, sprays, solid bars, emulsions,microemulsions and the like which can be formulated according to theconventional methods using suitable excipients, such as, for example,emulsifying agents, surfactants, thickeners, sun protection agents,wetting agents, cooling agents, skin relaxing agents, skin conditioningagents, skin protectors, emollients, wetting agents, dyes andcombinations of two or more of them.

The compounds and compositions of the invention can be administered bytransdermal route in the form of transdermal patches or iontophoresisdevices. Other components can optionally be incorporated in thetransdermal patches. For example, compositions and/or transdermalpatches can be formulated with one or more preservatives orbacteriostatic agents including but not limited to methylhydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkoniumchloride and the like. Fabric pads or balls of a bandage-type material,for example gauze, can be impregnated with the compositions in solution,lotion, cream, ointments or other form which can also be used fortopical application. In an embodiment, the compositions of the inventionare administered in the form of a transdermal patch. In anotherembodiment, the compositions of the invention are administered in theform of a sustained release transdermal patch. The transdermal patchesof the invention can include any conventional form such as, for example,an adhesive matrix, a polymeric matrix, a patch with a deposit, amatrix-type or monolithic laminated structure, and they are generallyformed by one or more reinforcing layers, adhesives, penetrationenhancers, an optional membrane controlling the rate, and a releasecoating which is removed to expose the adhesives before the application.The polymeric matrix patches also comprise a material forming apolymeric matrix. Suitable transdermal patches are described in moredetail in, for example, U.S. Pat. Nos. 5,262,165, 5,948,433, 6,010,715and 6,071,531, the entire descriptions of which are incorporated herein.

The compositions of this invention can additionally include conventionalexcipients, i.e. pharmaceutically acceptable organic or inorganicsubstance carriers, suitable for the parenteral application that do notdangerously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, saline solutions,alcohol, vegetable oils, polyethyleneglycols, gelatin, lactose, amylose,magnesium stearate, talc, surfactants, silicic acid, viscous paraffin,perfuming oil, monoglycerides and diglycerides of fatty acids,petroethral fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone and the like. The pharmaceutical preparations canbe sterilized and, if desired, mixed with auxiliary agents, for example,lubricants, preservatives, stabilizers, wetting agents, emulsifyingagents, salts for affecting osmotic pressure, buffers, dyes, flavoringagents and/or aromatic substances and the like which do not dangerouslyreact with the active compounds. For parenteral application, theparticularly suitable carriers consist of preferably oily or aqueoussolutions, as well as suspensions, emulsions or implants. The aqueoussuspensions can contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethylcellulose,sorbitol and/or dextran. The suspension can also optionally containstabilizers.

If desired, the composition can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation or powder. The composition can beformulated as a suppository, with traditional binding agents andcarriers such as triglycerides. The oral formulations can includeconventional carriers such as pharmaceutical grade mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate and the like.

Different delivery systems are known and can be used to administer thecompounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered insingle unit form or in sustained release form.

The suitable sustained release forms as well as the materials andmethods for their preparation are described in, for example,“Modified-Release Drug Delivery Technology”, Rathbone, M. J. Hadgraft,J. and Roberts, M. S. (eds.), Marcel Dekker, Inc., New York (2002);“Handbook of Pharmaceutical Controlled Release Technology”, Wise, D. L.(ed.), Marcel Dekker, Inc. New York, (2000); “Controlled Drug Delivery”,vol. 1, Basic Concepts, Bruck, S. D. (ed.), CRC Press Inc., Boca Raton(1983) and of Takada, K. and Yoshikawa, H., “Oral Drug delivery”,Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (ed.), JohnWiley & Sons, Inc., New York (1999), vol. 2, 728-742; Fix, J., “Oraldrug delivery, small intestine and colon”, Encyclopedia of ControlledDrug Delivery, Mathiowitz, E. (ed.), John Wiley & Sons, Inc., New York(1999), vol. 2, 698-728; the entire descriptions of which areincorporated herein as a reference.

In an embodiment of the invention, the oral administration form of thecompounds of 2,5-dihydroxybenzene is in a sustained release formadditionally comprising at least one coating or matrix. The sustainedrelease coating or matrix includes but is not limited to natural,semi-synthetic or synthetic polymers insoluble in water, modifiedpolymers, waxes, fats, fatty alcohols, fatty acids, natural,semi-synthetic or synthetic plasticizers, or a combination of two ormore of them.

Suitable polymers insoluble in water include but are not limited toacrylic resins such as, for example, poly(meth)acrylates,polyalkyl(C₁₋₄)-(meth)acrylates,polydialkyl(C₁₋₄)aminoalkyl(C₁₋₄)-(meth)acrylates and/or copolymers andthe like, and combinations of two or more of them; of ethyl acrylate andmethyl methacrylate copolymers with a 2:1 molar monomer ratio (EUDRAGITNE30D®), ethyl acrylate, methyl methacrylate and triethylammonium ethylmethacrylate chloride copolymers with a 1:2:0.1 molar monomer ratio(EUDRAGIT RS®), ethyl acrylate, methyl methacrylate and triethylammoniumethyl methacrylate chloride copolymers with a 1:2:0.2 molar monomerratio (EUDRAGIT RL®) and the like, and combinations of two or more ofthem.

Suitable polymers insoluble in water include but are not limited tocellulose derivatives, such as, for example, alkylcelluloses,ethylcellulose, cellulose esters, cellulose acetate, AQUACOAT®,SURELEASE® and the like.

Suitable natural, semisynthetic or synthetic waxes, fats or fattyalcohols include but are not limited to carnauba wax, beeswax, glycerolmonostearate, glycerol monobehenate, glycerol ditripalmitostearate,microcrystalline wax, cetyl alcohol, cetylstearyl alcohol and the like,and combinations of two or more of them.

Suitable plasticizers include but are not limited to lipophilic diestersof an aliphatic or aromatic C₆-C₄₀ dicarboxylic acid, C₁-C₈ aliphaticalcohols, such as, for example, dibutyl phthalate, diethyl phthalate,dibutyl sebacate, diethyl sebacate and the like; hydrophilic orlipophilic citric acid esters, such as, for example, triethyl citrate,tributyl citrate, acetyltributyl citrate, acetyltriethyl citrate and thelike; polyethyleneglycols, propyleneglycols, glycerol esters, such as,for example, triacetine, MYVACET® (acetylated mono and diglycerides,C₂₃H₄₄O₅ to C₂₅H₄₇O), triglycerides of medium chain length (MIGLYOL®),oleic acid or mixtures of at least two of said plasticizers. Thesustained release formulations can comprise one or more plasticizers inamounts of approximately 5 to approximately 50% by weight, based on theamount of polymer(s) used.

The sustained release formulations can also comprise other conventionalexcipients known by persons skilled in the art, such as, for example,lubricants, colored pigments, surfactants and the like. The sustainedrelease formulations can also contain an enteric coating, such that theyare gastroresistant.

Suitable enteric coatings include but are not limited to methacrylicacid/methyl methacrylate copolymers with a 1:1 molar monomer ratio(EUDRAGIT L®), methacrylic acid/methyl methacrylate copolymers with a1:2 molar monomer ratio (EUDRAGIT S®), methacrylic acid/ethyl acrylatecopolymers with a 1:1 molar monomer ratio (EUDRAGIT L30D-55®),methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a7:3:1 molar monomer ratio (EUDRAGIT FS®), shellac,hydroxypropylmethylcellulose, acetate-succinates, celluloseacetate-phthalates or a combination of two or more of them. Theseenteric coatings can also be optionally used in combination with thewater-insoluble poly(meth)acrylates described herein. In one embodiment,the enteric coatings are used in combination with EUDRAGIT NE30D® and/orEUDRAGIT RL® and/or EUDRAGIT RS®.

The enteric coatings can be applied using conventional processes knownby persons skilled in the art, as described in, for example, Johnson, J.L., “Pharmaceutical tablet coating”, Coatings Technology Handbook(Second Edition), Satas, D. and Tracton, A. A. (eds), Marcel Dekker,Inc. New York, (2001), 863-866; Carstensen, T., “Coating Tablets inAdvanced Pharmaceutical Solids”, Swarbrick, J. (ed.), Marcel Dekker,Inc. New York (2001), 455-468; Leopold, C. S., “Coated dosage forms forcolon-specific drug delivery”, Pharmaceutical Science & TechnologyToday, 2 (5), 197-204 (1999), Rhodes, C. T. and Porter, S.C., Coatings,in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (ed.), JohnWiley & Sons, Inc., New York (1999), vol. 1, 299-311; the entiredescriptions of which are incorporated herein as a reference.

In one embodiment of the invention, the sustained release formulationscomprising at least one 2,5-dihydroxybenzene compound of the inventionare in an immediate release form and in a sustained release form in thesame formulation. The formulation can additionally comprise at leastadditional one therapeutic agent, such as, for example, chemotherapeuticagents, steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, and combinations of two or more of them.

Although individual needs may vary, the determination of the optimalranges for effective amounts of the compounds and/or compositions ispart of the common experience of persons skilled in the art. Generally,the necessary dosage for providing an effective amount of the compoundsand compositions, which can be adjusted by a person skilled in the art,will vary depending on age, health, physical condition, gender, diet,weight, degree of the disorder of the receptor, treatment frequency andnature and scope of the disorder or disease, medical condition of thepatient, the administration route, pharmacological considerations suchas activity, efficacy, pharmacokinetic profile and of toxicology of theparticular compound used, if a drug delivery system is used, and if thecompound is administered as part of a combination of drugs.

The amount of a given 2,5-dihydroxybenzene compound that will beeffective in treating a particular disorder or condition will depend onthe nature of the disorder or condition, and can be determined byconventional clinical techniques, including the reference to Goodman andGilman, above; The Physician's Desk Reference, Medical EconomicsCompany, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons,Inc., St. Louis, Mo., 1993; the entire descriptions of which areincorporated herein as a reference. The exact dose to be used in theformulation will also depend on the administration route and theseverity of the disease or disorder, and must be chosen by the physicianand in accordance with the patient's circumstances. The duration oftreatment will typically depend on the particular condition, itsseverity, the condition of the patient, and the like, and will readilybe determined by one of skill in the art. Illustrative courses oftherapy include 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3.5 months, 4months, 4.5 months, 5 months, 6 months, 9 months, a year, or longer asneeded.

In treating a subject suffering from a disorder described herein,treatment may be continued until at least a 10% improvement is effectedin a symptom associated with the condition. In other embodiments,treatment is continued until the subject in need of such treatmentexperiences an improvement of at least about 20%, at least about 30%, atleast about 40%, preferably at least about 50%, preferably at leastabout 60%, more preferably at least about 70%, more preferably at leastabout 80%, even more preferably 90% or greater in a symptom associatedwith a disorder described herein.

In a particular embodiment of the invention, a compound of formula (I)is administered at least once per week. In other embodiments, a compoundof formula (I) is administered at least once per day. In yet otherembodiments, a compound of formula (I) is administered twice per day. Inanother particular embodiment, a compound of formula (I) is administeredover a period of at least about one week. In other embodiments, acompound of formula (I) is administered over a period of at least aboutfour weeks.

Therapeutic amounts can be empirically determined and will vary with theparticular condition being treated, the subject, the particularformulation components, dosage form, and the like.

In a particular embodiment, a compound of formula (I) is present in apharmaceutical composition in an amount of at least about 1% w/w. Inother embodiments, a compound of formula (I) is present in apharmaceutical composition in an amount of at least about 2.5% w/w, atleast about 5% w/w, at least about 10% w/w, or at least about 15% w/w.

In one embodiment, the 2,5-dihydroxybenzene compounds of Formula (I) canbe administered by transdermal, oral, buccal, parenteral, rectal routeor by inhalation in an amount of approximately 0.05 g a day toapproximately 50 g a day. In particular embodiments, the2,5-dihydroxybenzene compounds of Formula (I) can be administered bytransdermal, oral, buccal, parenteral, rectal, intraocular or oticalroute or by inhalation in an amount of approximately 0.10 g a day toapproximately 25 g a day. In more particular embodiments, the2,5-dihydroxybenzene compounds of Formula (I) can be administered bytransdermal, oral, buccal, parenteral, rectal, intraocular or oticalroute or by inhalation in an amount of approximately 0.25 g a day toapproximately 10 g a day. In a more particular embodiment, the2,5-dihydroxybenzene compounds of Formula (I) can be administered in anamount of approximately 0.5 g a day to approximately 5 g a day. In aneven more particular embodiment, the 2,5-dihydroxybenzene compounds ofFormula (I) can be administered in an amount of approximately 0.75 g aday to approximately 2.5 g a day. In another particular embodiment, the2,5-dihydroxybenzene compounds of Formula (I) can be administered in anamount of approximately 1 g a day to approximately 1.5 g a day. Theparticular amounts of the 2,5-dihydroxybenzene compounds of Formula canbe administered in the form of a single dose once a day; or in multipledoses several times throughout the entire day; or as a sustained releaseoral formulation. In one embodiment of the invention, approximately 50g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 g of the2,5-dihydroxybenzene compounds of Formula (I) are administered once aday (q.d) by transdermal, oral, buccal, parenteral, rectal, intraocularor otical route or by inhalation. In another embodiment of theinvention, approximately 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25g or 0.1 g of the 2,5-dihydroxybenzene compounds of Formula (I) areadministered twice a day (b.i.d) by transdermal, oral, buccal,parenteral, rectal, intraocular or otical route or by inhalation. Inanother embodiment of the invention, approximately 50 g, 25 g, 10 g, 5g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 g of the 2,5-dihydroxybenzenecompounds of Formula (I) are administered three times a day (t.i.d.) bytransdermal, oral, buccal, parenteral, rectal, intraocular or oticalroute or by inhalation. In another embodiment of the invention,approximately 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 gof the 2,5-dihydroxybenzene compounds of Formula (I) are administeredfour times a day by transdermal, oral, buccal, parenteral, rectal,intraocular or otical route or by inhalation.

In particular embodiments, the compounds of 2,5-dihydroxybenzene ofFormula (I) can be administered by topical route in a formulationcomprising an amount of approximately 0.001% to approximately 30% (w/w)of the 2,5-dihydroxybenzene compounds of Formula (I). In a moreparticular embodiment, the 2,5-dihydroxybenzene compounds of Formula (I)can be administered by topical route in a formulation comprising anamount of approximately 0.01% to approximately 20% (w/w) of the2,5-dihydroxybenzene compounds of Formula (I). In an even moreparticular embodiment, the 2,5-dihydroxybenzene compounds of Formula (I)can be administered by topical route in a formulation comprising anamount of approximately 0.1% to approximately 15% (w/w) of the2,5-dihydroxybenzene compounds of Formula (I). In a more particularembodiment, the 2,5-dihydroxybenzene compounds of Formula (I) can beadministered by topical route in a formulation comprising an amount ofapproximately 0.5% to approximately 10% (w/w) of the2,5-dihydroxybenzene compounds of Formula (I). In another particularembodiment, the 2,5-dihydroxybenzene compounds of Formula (I) can beadministered by topical route in a formulation comprising an amount ofapproximately 1% to approximately 5% (w/w) of the 2,5-dihydroxybenzenecompounds of Formula (I). In a more particular embodiment, the2,5-dihydroxybenzene compounds of Formula (I) can be administered bytopical route in a formulation comprising an amount of approximately2.5% to approximately 4% (w/w) of the 2,5-dihydroxybenzene compounds ofFormula (I). The topical formulation comprising the 2,5-dihydroxybenzenecompounds of Formula (I) can be administered in the form of a singledose once a day; or in multiple doses several times throughout theentire day. In an embodiment of the invention, the topical formulationcomprising approximately 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or0.001% of the 2,5-dihydroxybenzene compounds of Formula (I) isadministered four times a day. In another embodiment of the invention,the topical formulation comprising approximately 30%, 20%, 15%, 10%, 5%,2.5%, 1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene compounds ofFormula (I) is administered three times a day. In yet another embodimentof the invention, the topical formulation comprising approximately 30%,20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the2,5-dihydroxybenzene compounds of Formula (I) is administered twice aday (b.i.d). In another embodiment of the invention, the topicalformulation comprising approximately 30%, 20%, 15%, 10%, 5%, 2.5%, 1%,0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene compounds of Formula(I) is administered once a day.

In yet other embodiments, the invention provides a kit or packagecomprising a compound of formula (I), in packaged form, accompanied byinstructions for use. The compound of formula (I) may be packaged in anymanner suitable for administration, so long as the packaging, whenconsidered along with the instructions for administration, indicates themanner in which the compound of formula (I) is to be administered.

For example, a kit may comprise a compound of formula (I) in unit dosageform, along with instructions for use. For example, such instructionsmay indicate that administration of a compound of formula (I) is usefulin the treatment of rosacea. The compound of formula (I) may be packagedin any manner suitable for administration. For example, when thecompound of formula (I) is in oral dosage form, e.g., is in the form ofa coated tablet, then the kit may comprise a sealed container of coatedtablets, blister strips containing the tablets, or the like.

Various embodiments according to the above may be readily envisioned,and would depend upon the particular dosage form, recommended dosage,intended patient population, and the like. The packaging may be in anyform commonly employed for the packaging of pharmaceuticals, and mayutilize any of a number of features such as different colors, wrapping,tamper-resistant packaging, blister packs or strips, and the like.

EXAMPLES

The following non-limiting examples additionally describe and enable aperson skilled in the art to prepare and use the present invention.

Example 1 Effect of 2,5-dihydroxybenzoate on fibrosis

Sterile gelatin sponges (1 mm³; Curaspon Dental, Clinimed Holding,Zwanenburg, The Netherlands) were subcutaneously implanted in the dorsalregion of the neck in Sprague-Dawley rats after the induction ofintraperitoneal anesthesia. The animals were split into two groups:group A, the sponges were moistened with 200 μl of saline solution whichcontained 25 μg/ml of heparin and 10 μg/ml of basic FGF (bFGF); group B,the sponges were moistened in the same solution as in group A, but whichsolution further contained 2,5-dihydroxybenzoate (100 μM). After 7 days,the sponges and the surrounding subcutaneous fat were removed andhistologically analyzed. The septa of connective tissue (fibroblasts,collagen fibers and elastic fibers) separating the adipose lobules fromone another were analyzed to demonstrate the antifibrotic effect of2,5-dihydroxybenzoate.

The combined application of bFGF and 2,5-dihydroxybenzoate in thegelatin sponges reduces bFGF-induced fibrosis, since the septa ofconnective tissue in the adipose tissue contain fewer fibroblasts when2,5-dihydroxybenzoate is present, as is shown in the comparison betweenFIG. 1A and FIG. 1B.

These data support the use of 2,5-dihydroxybenzene compounds fortreating both local and general fibrotic processes.

Example 2 2,5-dihydroxybenzoate inhibits glioma cell proliferation

The following example shows the efficacy of 2,5-dihydroxybenzoate toreduce the proliferative capacity of glioma cells and supports the useof the compound in treating gliomas.

The cell line used was rat glioma C6 cells. The cells were cultured aspreviously described (Cuevas P et al. Neurol Res, 2005). The cells werecultured as adherent cells in Dulbecco's modified Eagle's medium,supplemented with 7.5% (v/v) of fetal bovine serum, 10 μg/ml ofstreptomycin and 10 units/ml of penicillin. The tumor cells were seededin 24-well plates at a density of 10,000 cells/well, and were incubatedat 37° C. in a humidified chamber with 5% CO₂. Once adhered, the cellswere treated or not (controls) with 2,5-dihydroxybenzoate at 100, 200,500 or 1000 μM and they were allowed to proliferate for 48 h. After thistime the glioma cell proliferation was evaluated by means of stainingthe fixed cells with crystal violet. The number of cells is proportionalto the amount of retained dye, which was spectrophotometricallydetermined by measuring the absorbance at 595 nm once the dye wasextracted from the cells.

Treatment with 2,5-dihydroxybenzoate inhibited rat glioma C6 cellproliferation in a concentration-dependent manner, an effect which wasstatistically significant at the concentrations of 500 and 1000 μM (FIG.2).

Example 3 Effect of 2,5-dihydroxycinnamic acid on rat glioma C6 cellproliferation

The following example shows the efficacy of 2,5-dihydroxycinnamic acid(3-(2,5-dihydroxyphenyl)-2-propenoic acid; 2,5-DHC) to reduce theproliferative capacity of glioma cells and supports the use of thecompound in treating gliomas.

The cell line used was the C6 cell line and the experiment was carriedout as described in Example 2. Once adhered, the cells were treated ornot (controls) with increasing concentrations of 2,5-DHC (10, 25, 50 and100 μM) and they were allowed to proliferate for 48 h. After this timethe glioma cell proliferation was evaluated by means of staining thefixed cells with crystal violet. The number of cells is proportional tothe amount of retained dye, which was determined spectrophotometricallyby measuring absorbance at 595 nm once the dye was extracted from thecells. The 2,5-DHC, at the concentration of 50 μM reduced the C6 cellproliferation to less than half, while proliferation was reduced to onetenth in the presence of 100 μM of 2,5-DHC (FIG. 3).

Example 4 Effects of 2,5-dihydroxybenzene sulfonate and2,5-diacetoxybenzene sulfonate on progression of subcutaneous gliomasalready established in rats

Rat C6 glioma cells were cultured as previously described (Cuevas P etal. Neurol Res, 2005). The C6 cells cultured to confluence in 75 cm²flasks were removed and implanted under the abdominal skin inanesthetized rats. The existence of a tumor in the implantation area wasobserved five days after the implantation of the tumor cells. Only therats in which the existence of a tumor was observed were randomlyassigned to be treated with daily intraperitoneal injections of2,5-dihydroxybenzene sulfonate (DHBS; 100 mg/kg/day),2,5-diacetoxybenzene sulfonate (DABS; 100 mg/kg/day) or the carrier(0.9% NaCl). After 10 days of treatment, the subcutaneous gliomas wereremoved and their volume was calculated according to the formulaV=4/3π·(L/2)·(A/2)² (in mm³) where L is the larger diameter and A is thesmaller diameter, both expressed in mm.

In general terms, the size of the tumors obtained from the rats treatedwith the carrier was greater than that of those obtained from the ratstreated with DHBS or DABS (FIG. 4). Actually, the average size of thesubcutaneous gliomas obtained from the rats treated with DHBS was lessthan that of the rats treated with carrier, and this average volume waseven less in the rats treated with DABS (FIG. 5A). Furthermore, in thegroup of rats treated with DABS, despite the fact that all the rats hadestablished tumors prior to treatment, 4 rats were tumor-free whentreatment ended. In fact, a statistical probability analysis (χ² test)showed that there is a greater probability of being tumor-free in thegroup treated with DABS than in the group treated with DHBS (FIG. 5B).

This example demonstrates the inhibitory effect of 2,5-dihydroxybenzenesulfonate on the progression of already established heterotopic gliomasand that the administration of 2,5-acetoxybenzene sulfonate represents asignificant advantage over the administration of 2,5-dihydroxybenzenesulfonate on the treatment of these tumors.

Example 5 Effect of 2,5-diacetoxybenzene sulfonate on apoptosis ofsubcutaneous gliomas already established in rats

Tumor cells elude the programmed cell death process or apoptosis thatnormal cells experience. Apoptosis induction in tumor cells is one wayto confront the development of a tumor. To evaluate the effect ofpotassium 2,5-dihydroxybenzene sulfonate (DABS) on tumor cell apoptosis,6 μm thick sections of the subcutaneous gliomas described in example 4were made. The sections were stained with hematoxylin and eosin andobserved at a magnification of 313 times using immersion oil. In theseconditions, cell apoptosis is shown by the existence of apoptotic bodiesappearing as strongly chromogenic granules in the cell nucleus which isfrequently fragmented. As can be seen in FIG. 6A, the presence of tumorcells in the process of apoptosis is very scarce in the gliomas obtainedfrom rats treated only with the carrier. However, a large number oftumor cells in apoptosis can be observed in the tumors from rats treatedwith DABS (100 mg/kg/day) for 10 days (FIG. 6B).

This example shows the treatment capacity of DABS to promote apoptosisin tumor cells of already established subcutaneous gliomas, a propertywhich definitely contributes to the inhibitory effect of treatment withDABS on the growth of these tumors shown in the previous example.

Example 6 Effect of 2,5-diacetoxybenzene sulfonate on human tumor cellproliferation

The cell lines used were the human prostate cancer PC-3 cells and humanlung cancer A549 cells. 2000 cells were seeded per well in 96-wellplates and they were allowed to adhere overnight. Then the cells weretreated or not (controls) with potassium 2,5-diacetoxybenzene sulfonate(DABS) (1-200 μM) and they were allowed to proliferate for 96 h. Afterthis time, the PC-3 and A549 cell proliferation was evaluated bydetermining the final number of cells by means of the viability methodof yellow tetrazolium salt (XTT). The data were expressed as apercentage of the control (without treatment). As can be seen in FIG. 7,DABS caused a significant inhibition of human prostate cancer and lungcancer cell proliferation.

Example 7 Effect of 2,5-diacetoxybenzene sulfonate on the progression ofsubcutaneous tumors in a prostate cancer cell implantation model inathymic mice

5×10⁶ human prostate cancer PC-3 cells were subcutaneously injected inmale athymic mice (Nu/Nu) of 6-8 weeks of age and weighing 20-26 g. Tendays after the implantation of the tumor cells, the mice were randomlysplit into two groups: one of them received a daily injection ofpotassium 2,5-diacetoxybenzene sulfonate (DABS) by intraperitoneal routeat a dose of 100 mg/kg dissolved in saline (0.9% NaCl) whereas the othergroup received a daily injection of carrier (saline). The treatmentswere administered for 15 days. The volumes of the tumors induced by theimplantation of PC-3 cells were measured through the skin on alternatingdays using a Vernier caliper. The volume was calculated using theformula V=(D×2d)/2, where D is the larger diameter in mm, d is thesmaller diameter in mm and V is the volume in mm3. At the end oftreatment, the mice were sacrificed and the tumors were weighed. As canbe seen in FIG. 8A, treatment with DABS significantly reduced the humanprostate cell tumor growth in athymic mice. This inhibitory effect ofDABS on the tumor volume corresponds with a significant reduction of theweight of the extracted tumor when treatment ended in the group treatedwith DABS (FIG. 8B).

The 2,5-dihydroxybenzene sulfonate esters described in the presentinvention are not just prodrugs to finally administer2,5-dihydroxybenzene sulfonate. The following examples show that thesecompounds in a completely unexpected manner, have by themselvespharmacological actions of interest in the invention without needing tobe converted into 2,5-dihydroxybenzene sulfonate.

Example 8 Inhibition of the mitogenesis of fibroblasts induced by thefibroblast growth factor-1 (FGF-1)

The inhibition of mitogenesis induced by FGF-1 in quiescent cultures ofBalb/c 3T3 fibroblasts by 2-acetoxy-5-hydroxybenzene sulfonate (FIG. 9),5-acetoxy-2-hydroxybenzene sulfonate (FIG. 10) and 2,5-diacetoxybenzenesulfonate (FIG. 11) was observed. The evaluated compounds were used inthe form of potassium salt, except in the first case which used calciumsalt. The experiments were carried out as described in Fernandez-TorneroC et al. J Biol Chem, 2003.

Example 9 Effect of 2,5-dihydroxybenzene sulfonate monoesters on rat C6glioma cell proliferation

The following example shows the efficacy of 2,5-dihydroxybenzenesulfonic, potassium 2-acetoxy-5-hydroxybenzene sulfonate (2A-5HBS) andpotassium 5-acetoxy-2-hydroxybenzene sulfonate (5A-2HBS) monoesters toreduce the proliferative capacity of glioma cells and supports the useof the compound in treating gliomas.

The cell line used was the C6 cell line and the experiment was carriedout as described in examples 2 and 3. Once adhered, the cells weretreated or not (controls) with (5A-2HBS) (500 μM) or (2A-5HBS) (500 μM)and they were allowed to proliferate for 48 h. After this time theglioma cell proliferation was evaluated by means of staining the fixedcells with crystal violet. The number of cells is proportional to theamount of retained dye, which was determined spectrophotometrically bymeasuring the absorbance at 595 nm once the dye was extracted from thecells.

Both 2,5-dihydroxybenzene sulfonate, (5A-2HBS) and (2A-5HBS) monoesterscaused the inhibition of rat glioma cell proliferation (FIG. 12).

Example 10 Analysis of the structural interaction of2,5-dihydroxybenzene sulfonate esters with the fibroblast growthfactor-1 (FGF-1)

Based on the crystal diffraction of the FGF-1:2-acetoxy-5-hydroxybenzenesulfonic acid, FGF-1:5-acetoxy-2-hydroxybenzene sulfonic acid andFGF-1:2,5-diacetoxybenzene sulfonic acid complexes, the structures ofthe complexes were calculated and represented. FIGS. 13, 14 and 15,which show the surface of the dyed protein according to itselectrostatic potential (light grey, negative charge; dark grey,positive charge; white, regions with no charge), show the manner inwhich 2-acetoxy-5-hydroxybenzene sulfonic acid,5-acetoxy-2-hydroxybenzene sulfonic acid and 2,5-diacetoxybenzenesulfonic acid interact, respectively, with FGF-1. The electron densityof the compound, contoured at 1σ (FIGS. 13-15, panels C), allowedlocating and determining the orientations of the compounds with respectto the protein (FIGS. 13-15, panels A and B), as well as confirming thatthe compounds conserve the acetoxyl groups in positions 2, 5 and, 2 and5, respectively, when they bind to the protein. The compounds occupy asite that is very close to the one that has been described occupied by2,5-dihydroxybenzene sulfonic acid, the aromatic ring of which forms acation-π bond with the N^(ε) group of lysine 132, which is marked inFIGS. 13-15, panels A, as a reference.

Each patent, patent application, and publication cited or described inthe present application is hereby incorporated by reference in itsentirety as if each individual patent, patent application, orpublication was specifically and individually indicated to beincorporated by reference.

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. One skilledin the art will appreciate that numerous changes and modifications canbe made to the invention, and that such changes and modifications can bemade without departing from the spirit and scope of the invention. Thefull scope of the invention should be determined by reference to theclaims, along with their full scope of equivalents, and thespecification, along with such variations.

1. A method for the treatment or prophylaxis of rosacea, comprisingadministering topically to a subject in need thereof, an effectiveamount of a 2,5-dihydroxybenzene derivative represented by Formula (I)or a pharmaceutically acceptable salt, solvate, or isomer thereof,wherein the compound of Formula (I) is:

wherein: R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Z; Y is —SO₃H, —SO₃ ⁻.X⁺,—SO₃R₃, —PO₃H, —PO₃ ⁻.X⁺, or —PO₃R₃, wherein when Y is —SO₃H, —SO₃ ⁻.X⁺or —SO₃R₃, then R₉ and R_(9′) are independently selected from —OH and—OR₂, wherein at least one of R₉ and R_(9′) is a substituted orunsubstituted alkylsulfonyloxy group, a substituted or unsubstitutedarylsulfonyloxy group, a substituted or unsubstituted alkylcarbonyloxygroup or a substituted or unsubstituted arylcarbonyloxy group; Z is—SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃ ⁻.X⁺, —PO₃R₃, —CO₂H, —CO₂ ⁻.X⁺ or—CO₂R₃; X⁺ is an organic cation or an inorganic cation, such that thegeneral charge of the compound is neutral; R₉ and R_(9′) areindependently selected from —OH and —OR₂, wherein when R₉ and R_(9′) areboth —OR₂, then said R₉ and R_(9′) can be the same or different; R₂ is asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaryl group, a substituted or unsubstituted alkylsulfonyl group, asubstituted or unsubstituted arylsulfonyl group, a substituted orunsubstituted alkylcarbonyl group or a substituted or unsubstitutedarylcarbonyl group; R₃ is a substituted or unsubstituted alkyl group ora substituted or unsubstituted aryl group; a is a number selected from0, 1, 2, 3, 4, 5 and 6, provided that a is not 0 when Y is —SO₃H; and pis an integer selected from 0, 1, 2, 3, 4, 5 and
 6. 2. The method ofclaim 1, wherein R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y.
 3. The methodof claim 2, wherein Y is selected from —SO₃H, —SO₃ ⁻.X⁺, and —SO₃R₃. 4.The method of claim 2, wherein R₃ is selected from methyl and ethyl. 5.The method of claim 1, wherein R₉ and R_(9′) are, independently, asubstituted or unsubstituted alkylsulfonyloxy group, a substituted orunsubstituted arylsulfonyloxy group, a substituted or unsubstitutedalkylcarbonyloxy group or a substituted or unsubstituted arylcarbonyloxygroup.
 6. The method of claim 1, wherein R₂ is selected frommethylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl,benzyl and phenyl.
 7. The method of claim 1, wherein the compound ofFormula (I) is selected from the group consisting of:5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(acetyloxy)benzenehomosulfonic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2-(acetyloxy)-5-hydroxybenzoic acid; 5-(acetyloxy)-2-hydroxybenzoicacid; 2,5-bis(acetyloxy)benzoic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-(acetyloxy)-5-hydroxyhomobenzoic acid;5-(acetyloxy)-2-hydroxyhomobenzoic acid; 2,5-bis(acetyloxy)homobenzoicacid; 3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamicacid); 3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceuticallyacceptable salts and solvates thereof. 8-10. (canceled)
 11. The methodof claim 1, further comprising administration of at least one additionaltherapeutic agent.
 12. The method of claim 11, wherein the at least oneadditional therapeutic agent is selected from the group consisting of: asteroid; a retinoid; an antimicrobial compound; an antioxidant; ananti-inflammatory compound; a vitamin D analog; salicylic acid; anendothelin antagonist; an immunomodulating agent; an angiogenesisinhibitor; an inhibitor of FGF, VEGF, EGF or HGF; an inhibitor of anEGF, FGF, VEGF or HGF receptor; a tyrosine kinase inhibitor; a proteinkinase C inhibitor; metronidazole; dapsone; a vasoconstricting agent;and a combination of two or more thereof.
 13. The method of claim 12,wherein the at least one additional therapeutic agent is metronidazole.14. The method of claim 9, wherein the compound is administered at leastonce per week.
 15. The method of claim 14, wherein the compound isadministered at least once per day.
 16. The method of claim 15, whereinthe compound is administered at least twice per day.
 17. The method ofclaim 9, wherein the compound is present in a pharmaceutical compositionin an amount of at least about 1% w/w.
 18. The method of claim 17,wherein the compound is present in a pharmaceutical composition in anamount of at least about 2.5% w/w.
 19. The method of claim 18, whereinthe compound is present in a pharmaceutical composition in an amount ofat least about 5% w/w.
 20. The method of claim 19, wherein the compoundis present in a pharmaceutical composition in an amount of at leastabout 10% w/w.
 21. The method of claim 20, wherein the compound ispresent in a pharmaceutical composition in an amount of at least about15% w/w.
 22. The method of claim 9, wherein the compound is administeredover a period of at least about one week.
 23. The method of claim 22,wherein the compound is administered over a period of at least aboutfour weeks.
 24. (canceled)